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Liveblogging 1st Disclosures of Drug Candidates

UPDATE April 2: If you read this coverage please tell us what you thought about it here or in the comments.

1:26:15 PM: I’m @ Moscone Ctr in San Fran. T minus half hour to unveiling of new drug candidate structures. #acsmedi #acs_sf

1:37:35 PM: A hearty welcome to any readers of Totally Synthetic @Totsyn #acsmedi

2:01:50 PM: 1st: Albert J. Robichaud-of Lundbeck-on Pfizer’s $PFE SAM-531, 5-HT6 antagonist for schizophrenia, Alzheimer’s #acsmedi #acs_sf

2:02:53 PM: Alzheimer’s therapies today- palliative. Modulate eiether acetylcholine, glutamate #acsmedi #acs_sf

2:04:58 PM: ~45 million ppl with ALzheimer’s worldwide- patients have probs w learning,memory, reasoning #acsmedi #acs_sf

2:06:33 PM: 5HT6- 1 of 14 serotonin receptors- a G-protein coupled receptor #acsmedi #acs_sf

2:07:00 PM: block 5HT6- boosts levels of glutamate, acetylcholine neurotransmission in brain areas assoc w/learning, memory #acsmedi #acs_sf

2:09:37 PM: focus has been indole, azaindoles #acsmedi #acs_sf

2:09:47 PM: http://twitpic.com/1a3b3v – Lead

2:12:17 PM: SAR: aryl sulfonyl groups req’d for activity. Most substitution not good on indole NH. #acswmedi #acs_sf

2:15:13 PM: http://twitpic.com/1a3c9x – 531

2:16:59 PM: SAM-531 enhances memory retention in rodents in a test called novel object recognition #acsmedi #acs_sf

2:18:46 PM: SAM-531 potent selective 5HT6 antagonist. In phase II clinical development in patients with Alzheimer’s #acsmedi #acs_sf

2:21:00 PM: Q&A: what is brain to plasma ratio? speaker says less than 25%. But high enough for efficacy

2:22:20 PM: pKa of the amine in metabolites? HERG inhibition? pKa wasn’t known. No issues with HERG.

2:22:37 PM: Next: Thomas Simpson of AstraZeneca $AZN on AZD2624, NK3 receptor antagonist to test NK3 hypothesis in schizophrenia #acsmedi #acs_sf

2:22:46 PM: Astrazeneca on Twitter @AstraZenecaUS

2:23:22 PM: Schizophrenia: 2.2 million people in US have it #acsmedi #acs_sf

2:23:43 PM: Schiz. drugs (many are dopamine receptor antagonists) aren’t equally effective @ treating all symptoms #acsmedi #acs_sf

2:24:49 PM: NK3 blockers adjust dopamine levels by indirect mechanism- new opportunities #acsmedi #acs_sf

2:25:41 PM: Phase II studies on osanetant and talnetant- NK3r blockers- precedents in clinic #acsmedi #acs_sf

2:27:24 PM: both osenetant and talnetant are no longer in development- but support idea of NK3 #acsmedi #acs_sf

2:28:50 PM: Talnetant is a more druglike structure than osanetant #acsmedi #acs_sf

2:29:55 PM: Improve solubility and plasma protein binding of talnetant. A poster later today will outline early chem strategy. #acsmedi #acs_sf

2:32:32 PM: http://twitpic.com/1a3g8v – T

2:33:19 PM: http://twitpic.com/1a3gfd – O

2:33:42 PM: Patnent #s WO2006130080, 137789, WO200703528 #acsmedi, #acs_sf

2:35:44 PM: Sulfonate ester – this path leads to clinical candidate #acsmedi #acs_sf stability was an issue-hydrolysis

2:37:31 PM: http://twitpic.com/1a3hcu – Sulf es

2:38:49 PM: Alkylsulfonylamino groups- dramatic improvement in stability #acsmedi #acs_sf

2:39:52 PM: 2624- gerbil brain/plasma: 0.21 #acsmedi #acs_sf

2:40:12 PM: http://twitpic.com/1a3hyj – 2624

2:43:40 PM: Comparing a sulfoxide, AZD9122: half life (h): 2.8 rat, 6.7 dog. 2624 is better: 3.2 rat, 9.something in dog #acsmedi #acs_sf

2:45:22 PM: in monkeys: AZD2624 affect dopamine release measured by PET. Sulfoxide wasn’t as good in preclinical safety as 2624. #acsmedi #acs_sf

2:48:53 PM: Phase I clinical trials: 2624 is well tolerated in healthy ppl. testosterone reduction but no major adverse effects #acsmedi #acs_sf

2:50:37 PM: AZD2624 appears 2 cause testosterone reduction thru action @ hypothalamus #acsmedi #acs_sf

2:52:45 PM: Phase IIa trial: patients w schizophrenia:placebo,olanzapine,2624. #acsmedi #acs_sf

2:53:13 PM: 2624 failed to show efficacy @ dose just below what would cause testosterone fx #acsmedi #acs_sf

2:56:20 PM: $AZN has exited schizophrenia but 2624 may provide patient benefit via modulating neuroendocrine system #acsmedi #acs_sf

2:57:04 PM: other posters and talks in this area – MEDI-222, MEDI223, MEDI230, MEDI564 #acsmedi #acs_sf

3:00:07 PM: Q&A: PET study on patients too- ensure drug gets 2brain? A:was considered. but we know it gets to hypothal. #acsmedi #acs_sf

3:00:21 PM: Now-David Augeri Lexicon Pharmaceuticals $LXRX on LX2931, LX2932, S1P lyase inhibs for autoimmune disorders #acsmedi #acs_sf

3:00:33 PM: Lexicon on twitter @lexpharma

3:01:17 PM: Sphingosine-1-Phosphate (S1P)=important signaling ligand for human immune system #acsmedi #acs_sf

3:02:52 PM: S1P Lyase enzyme degrades S1P, downstream decrease in inflammatory response, fewer white blood cells in circulation #acsmedi #acs_sf

3:04:44 PM: Lexicon’s Genome 5000 Program:mouse w/out S1P lyase has fewer white blood cells in circ. they’re retained in thymus. #acsmedi #acs_sf $LXRX

3:06:23 PM: Starting point: food coloring compound THI- trace component of caramel color -has similar effect to KO of S1P lyase #acsmedi #acs_sf

3:08:56 PM: http://twitpic.com/1a3ofm – T

3:09:32 PM: Optimizing 3 areas of THI: poly-OH sidechain, imidazole core, C2 ketone #acsmedi #acs_sf

3:10:03 PM: Classic chem: team uses Amadori rearrangement and Buchi condensation to make THI analogs #acsmedi #acs_sf

3:12:06 PM: J Med Chem 2009, 52, 3941 – more on Amadori, Buchi #acsmedi #acs_sf

3:13:34 PM: http://twitpic.com/1a3pfs – No act

3:14:27 PM: Changes to core and hydroxyls not beneficial overall- C2 oxime- increased activity dramatically #acsmedi #acs_sf

3:15:38 PM: THI ketone: poor soluble as base. reactive under mild conditions-dimerizes. Oxime- potent, soluble, ez2 formulate, stable. #acsmedi #acs_sf

3:16:10 PM: Oxime is LX2931 #acsmedi #acs_sf

3:17:41 PM: How unique is 2931 activity? Tie up in heterocycle? Isoxazole-oxime isostere? #acsmedi #acs_sf

3:17:48 PM: http://twitpic.com/1a3qbg – 2931

3:19:49 PM: C2 oxazole and pyridine, no activity. isoxazole=LX2932- backup to 2931 #acsmedi #acs_sf

3:22:15 PM: http://twitpic.com/1a3r98 – 2

3:23:57 PM: LX2931Low doses work well in aggressive animal model – collagen induced arthritis #acsmedi #acs_sf

3:26:14 PM: Phase 1a trial: dose dependent decrease in lymphocyte (white blood cell) levels in patients #acsmedi #acs_sf -same as rodents, monkeys

3:27:23 PM: LX2931 is currently in Phase II clinical trials.- in patients with rheumatoid arthritis #acsmedi #acs_sf

3:30:53 PM: Q&A: what is the mechanism? direct effect on lyase? A:pursuing studies to nail down mechanism more fully

3:31:08 PM: Now Merck’s Paul Coleman shares the story of MK-4305, orexin receptor antagonist for treating insomnia #acsmedi #acs_sf

3:32:49 PM: Imsomnia: periodically affects 50% of adults #acsmedi #acs_sf

3:33:11 PM: most sleeping pills on market (eg Ambien Lunesta) adjust activity of GABA receptors #acsmedi #acs_sf

3:33:54 PM: But GABA–targetd compounds aren’t specific. FDA has issued warns:for allergy,behavior chgs,abnormal thinking #acsmedi #acs_sf

3:34:23 PM: Goal- provide restorative “natural” sleep, improve tolerability #acsmedi #acs_sf

3:35:14 PM: orexins=peptides in hypothalamus. orexin receptor=GPCR, connected to brain regions involved in wakefulness #acsmedi #acs_sf

3:37:35 PM: Actelion- clinical proof of concept with almorexant- targets orexin receptors #acsmedi #acs_sf

3:39:40 PM: PK is key- quick onset for sleep- but want the compound decaying at ~8hrs so no residuals on wakeup #acsmedi #acs_sf

3:41:12 PM: selected Assays: radioligand binding assay. Functional assay w/ calcium FLIPR , metabolite studies (important!) Pgp efflux,

3:41:51 PM: tetrahydroisoquinolines, proline amides, diazaspirodecanes among screening hits #acsmedi #acs_sf

3:42:11 PM: Two classes Merck followed up on from screens: http://bit.ly/cNyEo9 http://bit.ly/9Goj1p #acsmedi #acs_sf

3:42:25 PM: Focus is on the diazepanes #acsmedi #acs_sf

3:43:29 PM: Hit: 150nM at OX1, 3nM OX2. #acsmedi #acs_sf

3:44:09 PM: http://twitpic.com/1a3w7s – Hit

3:44:29 PM: Best heterocycle on eastern half- triazole #acsmedi #acs_sf methyl group- goes to 2.0nM, 0.6nM

3:46:17 PM: http://twitpic.com/1a3wpd – Lead

3:46:19 PM: lead=compound 9. #acsmedi #acs_sf cmpd9 doesn’t have great PK. , but demonstrated effects on orexin receptors.

3:47:39 PM: Conformational analysis of 9:low energy twist-boat structure. stab’d by pi-pi interaction #acsmedi #acs_sf Xray confirms

3:48:41 PM: PK of 9: oral bioavail less than 5% in rat. Radiolabel 9 for further studies #acsmedi #acs_sf

3:50:14 PM: metabolism-block sites of oxidation. stratgies- bridge- BMCL in press. or substituted diazepanes #acsmedi #acs_sf

3:52:54 PM: F on quinazoline wasn’t entirely beneficial- bioactivation. #acsmedi #acs_sf

3:56:10 PM: http://twitpic.com/1a3yul – 4305

3:57:14 PM: Gold standard EEG studies in rat with MK-4305- mouse implanted with EEG transmitter- what sleep stage is rat in? #acsmedi #acs_sf

3:57:51 PM: MK-4305 promotes sleep in rats dose-dependently. #acsmedi #acs_sf

3:59:22 PM: No clinical data was disclosed for MK-4305 #acsmedi #acs_sf

3:59:42 PM: MK-4305 is in Phase III clinical trials for treatment of insomnia. #acsmedi #acs_sf

4:01:39 PM: Q&A: any signs of cataplexy, side effects? A: cataplexy-loss of muscle tone as in narcolepsy, no sign of it #acsmedi #acs_sf

4:03:17 PM: In case you’re wondering, the 1st disclosures session has been packed throughout. #acsmedi #acs_sf

4:03:29 PM: Next up-BMS’s Paul Scola w/BMS-650032, NS3 protease inhibitor for Hepatitis C $BMY #acsmedi #acs_sf

4:03:47 PM: BMS on twitter – @bmsnews

4:05:36 PM: Hep C affects 3% of the world’s population, 10K deaths/yr #acsmedi #acs_sf

4:06:16 PM: HepC is leading cause of liver transplants. Virus lives in liver cells #acsmedi #acs_sf

4:06:53 PM: Today we treat HepC w/ribavirin and interferon. Nonspecific.Not equally effective for all patients. side fx-flulike symps #acsmedi #acs_sf

4:07:35 PM: $BMY – treatment will req a combo of agents. They are looking @ a # of targets #acsmedi #acs_sf

4:08:12 PM: NS3=serine protease. essential for viral replication #acsmedi #acs_sf

4:09:22 PM: BMS $BMY signature element=acylsulfonamide #acsmedi #acs_sf

4:10:18 PM: Acylsulfonamides preserve acidity of carboxylic acid at key pocket- near active site #acsmedi #acs_sf

4:10:47 PM: cyclopropylacylsulfonamide- most potent #acsmedi #acs_sf

4:12:17 PM: 781= early lead. develop SAR at various subsites. #acsmedi #acs_sf

4:12:19 PM: http://twitpic.com/1a42j5 – 781

4:14:28 PM: Small changes: change northern part of molecule to isoquinoline->inprovements in PK and liver levels #acsmedi #acs_sf

4:16:21 PM: put substitutents on isoquinoline- further improvements. ->BMS-605339 #acsmedi #acs_sf

4:17:45 PM: http://twitpic.com/1a43sx – 605339

4:17:55 PM: 605339- sustained liver levels after oral dosing to rats, dogs. levels in spleen, heart similar to plasma #acsmedi #acs_sf

4:18:38 PM: Animal models suggested a suitable safety window for 605339 #acsmedi #acs_sf

4:19:44 PM: Clinical data 605339: ECG changes caused $BMY to terminate study. Mild bradycardia #acsmedi #acs_sf

4:20:57 PM: ECG- electrocardiogram. bradycardia- slowing of the heart rate #acsmedi #acs_sf

4:22:11 PM: Next-gen compounds ID’d via isolated rabbit heart model that recaps ECG events in lab #acsmedi #acs_sf

4:23:42 PM: small changes to isoquinoline:minimize cardiovas effects. Focused on 6,6 fused heterocycles. #acsmedi #acs_sf

4:27:00 PM: I’ve twted the change to the isoquinoline in 605339- full structure soon #acsmedi #acs_sf

4:27:16 PM: http://twitpic.com/1a45zh – 605339

4:29:09 PM: 650032:potent antiviral activity after single doses. safety profile good. #acsmedi #acs_sf

4:32:31 PM: Last talk: John K. Walker from $PFE on S1P receptor agonist for treating rheumatoid arthritis #acsmedi #acs_sf

4:33:09 PM: Rheumatoid arthritis(RA)=autoimmune disease. Affects 2.1million Americans #acsmedi #acs_sf

4:33:52 PM: RA meds=mostly biologics. Expense, effectiveness vary. #acsmedi #acs_sf

4:34:47 PM: Recall from $LXRX @lexpharma talk; (S1P)=important signaling ligand for immune system #acsmedi #acs_sf

4:36:41 PM: Novartis’ fingolimod, targets S1P1- in Phase III trials for m.sclerosis- http://bit.ly/17rfX #CENews #acsmedi #acs_sf

4:36:51 PM: Fingolimod isn’t selective-hits S1P3 in heart tissues-can slow heart rate #acsmedi #acs_sf

4:38:54 PM: Starting point: 2005 report from Merck #acsmedi #acs_sf

4:40:30 PM: http://twitpic.com/1a493s – Start

4:41:47 PM: Team examined wide range of compounds to see what was needed for reducing lymphocytes in circulation #acsmedi #acs_sf

4:43:19 PM: aminocyclobutane was optimum- cis better than trans #acsmedi #acs_sf

4:45:38 PM: 591= lead #acsmedi #acs_sf. further modifications to “tail” at west end of molecule #acsmedi #acs_sf

4:47:30 PM: http://twitpic.com/1a4asd -

4:49:22 PM: endgame- success-add alpha methyl next to “a” ring #acsmedi #acs_sf

4:50:46 PM: 991- rat PK and lymphopenia data- improved PK parameters- T1/2 = 5.2hrs #acsmedi #acs_sf

4:50:55 PM: http://twitpic.com/1a4bl5 – 991

4:51:25 PM: 991 was advanced to Phase I clinical trials at beginning of last year #acsmedi #acs_sf

4:51:47 PM: full name- PF-991 #acsmedi #acs_sf

4:53:13 PM: CORRECTION to 4:27:16- that picture is of a portion of BMS-650032. NOT 605339. #acsmedi #acs_sf

4:59:22 PM: That’s it! Thanks everyone for following along. I’ll double check on BMS-650032 struc.&get it to you ASAP. #acsmedi #acs_sf

5:12:51 PM: Got the structure of BMS-650032 coming up #acsmedi #acs_sf

5:14:28 PM: http://twitpic.com/1a4h0q – 650032

5:16:33 PM: @samjlord @egonwillighagen thx for the help- i’m still learning here. geotagging sounds fascinating

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